Identification of Anti-virulence Compounds That Disrupt Quorum-Sensing Regulated Acute and Persistent Pathogenicity

Starkey, Mélissa; Lépine, François; Maura, Damien; Bandyopadhaya, Arunava; Lesic, Biliana; He, Jianxin; Kitao, Tomoe; Righi, Valéria; Milot, Sylvain; Tzika, A. Aria; Rahme, Laurence G.

doi:10.1371/journal.ppat.1004321

Cited by 227 publications

(307 citation statements)

References 84 publications

(139 reference statements)

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“…Given the large number of potential protein targets known to regulate EPS production through the GacAS pathway, further work is needed to identify the specific antibiofilm target and to elucidate a defined mechanism of action for the identified molecules. Antivirulence compounds have been described for P. aeruginosa that target the quorum-sensing Las, Rhl, and Pqs systems (55,56). This work supports the hypothesis that the pel and psl EPS biosynthesis genes provide a new target for antivirulence drug development.…”

Section: Discussionsupporting

confidence: 66%

Exopolysaccharide-Repressing Small Molecules with Antibiofilm and Antivirulence Activity against Pseudomonas aeruginosa

Bernardes

Charron-Mazenod

Reading

et al. 2017

Antimicrob Agents Chemother

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Biofilm formation is a universal virulence strategy in which bacteria grow in dense microbial communities enmeshed within a polymeric extracellular matrix that protects them from antibiotic exposure and the immune system. Pseudomonas aeruginosa is an archetypal biofilm-forming organism that utilizes a biofilm growth strategy to cause chronic lung infections in cystic fibrosis (CF) patients. The extracellular matrix of P. aeruginosa biofilms is comprised mainly of exopolysaccharides (EPS) and DNA. Both mucoid and nonmucoid isolates of P. aeruginosa produce the Pel and Psl EPS, each of which have important roles in antibiotic resistance, biofilm formation, and immune evasion. Given the central importance of the EPS for biofilms, they are attractive targets for novel anti-infective compounds. In this study, we used a high-throughput gene expression screen to identify compounds that repress expression of the pel genes. The pel repressors demonstrated antibiofilm activity against microplate and flow chamber biofilms formed by wild-type and hyperbiofilm-forming strains. To determine the potential role of EPS in virulence, pel/psl mutants were shown to have reduced virulence in feeding behavior and slow killing virulence assays in Caenorhabditis elegans. The antibiofilm molecules also reduced P. aeruginosa PAO1 virulence in the nematode slow killing model. Importantly, the combination of antibiotics and antibiofilm compounds increased killing of P. aeruginosa biofilms. These small molecules represent a novel anti-infective strategy for the possible treatment of chronic P. aeruginosa infections.

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Section: Discussionsupporting

confidence: 66%

Exopolysaccharide-Repressing Small Molecules with Antibiofilm and Antivirulence Activity against Pseudomonas aeruginosa

Bernardes

Charron-Mazenod

Reading

et al. 2017

Antimicrob Agents Chemother

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“…Another target-based approach led to the identification of a group of quorum-sensing (QS) inhibitors that specifically target the P. aeruginosa MvfR system. Besides disrupting cell-to-cell communication and decreasing infection, these compounds were the first molecules identified to limit the formation of persister cells in P. aeruginosa (36).…”

Section: Discussionmentioning

confidence: 99%

Identification of 1-((2,4-Dichlorophenethyl)Amino)-3-Phenoxypropan-2-ol, a Novel Antibacterial Compound Active against Persisters of Pseudomonas aeruginosa

Liebens

Defraine

Knapen

et al. 2017

Antimicrob Agents Chemother

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Antibiotics typically fail to completely eradicate a bacterial population, leaving a small fraction of transiently antibiotic-tolerant persister cells intact. Persisters are therefore seen to be a major cause of treatment failure and greatly contribute to the recalcitrant nature of chronic infections. The current study focused on Pseudomonas aeruginosa, a Gram-negative pathogen belonging to the notorious ESKAPE group of pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) and, due to increasing resistance against most conventional antibiotics, posing a serious threat to human health. Greatly contributing to the difficult treatment of P. aeruginosa infections is the presence of persister cells, and elimination of these cells would therefore significantly improve patient outcomes. In this study, a smallmolecule library was screened for compounds that, in combination with the fluoroquinolone antibiotic ofloxacin, reduced the number of P. aeruginosa persisters compared to the number achieved with treatment with the antibiotic alone. Based on the early structure-activity relationship, 1-((2,4-dichlorophenethyl)amino)-3-phenoxypropan-2-ol (SPI009) was selected for further characterization. Combination of SPI009 with mechanistically distinct classes of antibiotics reduced the number of persisters up to 10 6 -fold in both lab strains and clinical isolates of P. aeruginosa. Further characterization of the compound revealed a direct and efficient killing of persister cells. SPI009 caused no erythrocyte damage and demonstrated minor cytotoxicity. In conclusion, we identified a novel antipersister compound active against P. aeruginosa with promising applications for the design of novel, case-specific combination therapies in the fight against chronic infections.

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“…Recently, the hipAB system of Shewanella oneidensis was characterized, and a ternary HipAB-DNA complex different from the one from E. coli was observed (46). Since persister cells are highly problematic with respect to antibiotic treatments of infectious diseases, much emphasis has been placed on the development of drugs that suppress the development and survival of persister cells (47)(48)(49)(50)(51)(52)(53).…”

Section: Persister Cells As a Classical Model For Phenotypic Heterogementioning

confidence: 99%

Phenotypic Heterogeneity, a Phenomenon That May Explain Why Quorum Sensing Does Not Always Result in Truly Homogenous Cell Behavior

Grote

Krysciak

Streit

2015

Appl Environ Microbiol

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Phenotypic heterogeneity describes the occurrence of "nonconformist" cells within an isogenic population. The nonconformists show an expression profile partially different from that of the remainder of the population. Phenotypic heterogeneity affects many aspects of the different bacterial lifestyles, and it is assumed that it increases bacterial fitness and the chances for survival of the whole population or smaller subpopulations in unfavorable environments. Well-known examples for phenotypic heterogeneity have been associated with antibiotic resistance and frequently occurring persister cells. Other examples include heterogeneous behavior within biofilms, DNA uptake and bacterial competence, motility (i.e., the synthesis of additional flagella), onset of spore formation, lysis of phages within a small subpopulation, and others. Interestingly, phenotypic heterogeneity was recently also observed with respect to quorum-sensing (QS)-dependent processes, and the expression of autoinducer (AI) synthase genes and other QS-dependent genes was found to be highly heterogeneous at a single-cell level. This phenomenon was observed in several Gram-negative bacteria affiliated with the genera Vibrio, Dinoroseobacter, Pseudomonas, Sinorhizobium, and Mesorhizobium. A similar observation was made for the Gram-positive bacterium Listeria monocytogenes. Since AI molecules have historically been thought to be the keys to homogeneous behavior within isogenic populations, the observation of heterogeneous expression is quite intriguing and adds a new level of complexity to the QS-dependent regulatory networks. All together, the many examples of phenotypic heterogeneity imply that we may have to partially revise the concept of homogeneous and coordinated gene expression in isogenic bacterial populations. Bacteria have evolved multiple strategies to cope with rapid and frequent changes in their environment. These survival strategies may include spore formation, increased production of polysaccharides, biofilm formation or escape from biofilms (i.e., switching from a motile into a sessile form and vice versa), altered motility, change of metabolic capabilities, response to antibiotics, and many more. In general, these switches are initiated by environmental or bacterially produced signals that are perceived by a diverse array of regulators and delegated into the corresponding regulatory networks. This presumably results in altered transcription levels of different genes or operons, which eventually causes a change in the phenotype and a response to the environmental stimulus. Within this context, it is generally assumed that the majority of a population will undergo this switch within a short time period and that the population will show a mostly homogeneous expression profile. During the last decade, it became, however, evident that a certain fraction of cells in an isogenic population behaves differently from the others, even though the environment may not have changed significantly. The term "phenotypic heterogeneity" thereby descr...

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Identification of Anti-virulence Compounds That Disrupt Quorum-Sensing Regulated Acute and Persistent Pathogenicity

Cited by 227 publications

References 84 publications

Exopolysaccharide-Repressing Small Molecules with Antibiofilm and Antivirulence Activity against Pseudomonas aeruginosa

Exopolysaccharide-Repressing Small Molecules with Antibiofilm and Antivirulence Activity against Pseudomonas aeruginosa

Identification of 1-((2,4-Dichlorophenethyl)Amino)-3-Phenoxypropan-2-ol, a Novel Antibacterial Compound Active against Persisters of Pseudomonas aeruginosa

Phenotypic Heterogeneity, a Phenomenon That May Explain Why Quorum Sensing Does Not Always Result in Truly Homogenous Cell Behavior

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